WO2007060802A1

WO2007060802A1 - Solid pharmaceutical preparation and pharmaceutical preparation composition

Info

Publication number: WO2007060802A1
Application number: PCT/JP2006/321101
Authority: WO
Inventors: Masanobu Yamamoto; Kimihito Torii; Nobutaka Abe; Takehiko Horio; Yuri Matsuura
Original assignee: Ono Pharmaceutical Co., Ltd.
Priority date: 2005-11-24
Filing date: 2006-10-24
Publication date: 2007-05-31
Also published as: KR20080071557A

Abstract

It is intended to provide a solid pharmaceutical preparation and a pharmaceutical preparation composition containing a stable pranlukast hydrate which elutes quickly and in which the elution rate thereof is not likely to change even if it is stored in an unpacked condition. A granulated substance contains 0.02 to 0.15 part by weight of low-substituted hydroxypropylcellulose and 0.1 to 0.6 part by weight of one or more excipients selected from lactose, white soft sugar and mannitol relative to 1 part by weight of the pranlukast hydrate, elutes quickly, shows a stable elutability and has a small change in the elution rate with time.

Description

Specification

Solid formulations and pharmaceutical compositions

Technical field

[0001] The present invention comprises pranlukast hydrate, a cellulosic disintegrant and an excipient, which dissolves rapidly, exhibits stable dissolution, and has little change in dissolution rate over time. The present invention relates to a granulated product suitable for solid preparations!

Background art

[0002] Pranlukast hydrate is known as a leukotrien antagonist (see Patent Document 1), and a capsule (trade name: ononcapsell) or dry syrup containing pranlukast hydrate as an active ingredient (Product name: Onon Dry Syrup) is listed. Pranlukast hydrate-containing preparations are very useful as treatments for bronchial asthma and allergic rhinitis.

[0003] On the other hand, onon capsules have been reported to undergo dissolution changes in one week when stored in an unwrapped state at a temperature of 25 ° C and a relative humidity of 75% (see Non-Patent Document 1). On the other hand, a formulation containing pranlukast obtained by stirring granulation of pranlukast hydrate and a hydrogel-forming substance that can minimize dissolution changes even when stored without packaging is reported. Has been. However, it is described that the formulation has a slow elution of the active ingredient, for example, the dissolution rate at 120 minutes after the start of the dissolution test is 34.0% (see Patent Document 2).

[0004] In pharmaceuticals, it is known that a long time required for elution of an active ingredient, that is, a slow elution, adversely affects the blood concentration and bioavailability of the active ingredient. Therefore, the development of a drug product in which pranlukast hydrate dissolves quickly is very important for quality assurance as a pharmaceutical product.

[0005] As a general and simple method for improving the dissolution property, it is known to add celluloses as a disintegrant. Cellulose is also used as a binder because of its high moldability (high viscosity). On the other hand, pranlukast hydrate is known to have very strong adhesion (Patent Document 3). Therefore, if a granulated product is prepared by combining pranlukast hydrate and celluloses to improve dissolution, pranlukast hydrate Due to the relationship between the properties of cellulose and cellulose, there is a concern about the further increase (deterioration) in the adhesion (aggregation) of granulating powder (granulated material), and the formulation of pranlukast hydrate with improved dissolution is It was considered very difficult.

Patent Document 1: Japanese Patent Application Laid-Open No. 61-050977 (Claims)

Patent Document 2: JP-A-2005-187406 (Claims, Examples)

Patent Document 3: Japanese Patent No. 2958863 (paragraph [0004])

Non-Patent Document 1: Tablet 'Capsule Stability Information in Unwrapped State Revised 3rd Edition (Japan Hospital, Pharmaceutical Journal) (page 136)

Disclosure of the invention

Problems to be solved by the invention

[0007] An object of the present invention is to provide a granulated material containing a stable pranlukast hydrate, in which the active ingredient is rapidly eluted and hardly changes in the dissolution rate even when stored in an unwrapped state. It is to provide a pharmaceutical composition.

Means for solving the problem

[0008] As a result of intensive studies, the inventors of the present invention prepared a granulated product by combining pranlukast hydrate with a specific cellulose-based disintegrant and an excipient. In particular, the elution property of pranlukast hydrate can be improved by making the content of the cellulose-based disintegrant with respect to pranlukast hydrate a specific value in the granulated product. I found that it can be improved. Furthermore, the present inventors have found that the granulated product found above and a pharmaceutical composition containing the same exhibit stable dissolution and little change in dissolution rate over time, thereby completing the present invention. .

[0009] That is, the present invention provides

[1] One part or more selected from the group consisting of 0.02-0.15 parts by weight of low-substituted hydroxypropyl cellulose and 1 part by weight of pranlukast hydrate and lactose, sucrose, and mantolka Containing 0.1 to 0.6 parts by weight of the above-mentioned excipient, which dissolves rapidly, exhibits stable dissolution, and shows little change in dissolution rate over time.

[2] The granulated product according to [1], further containing a binder,

[3] The granulated product according to [1], wherein the average tensile breaking force is 300 to 600 g, [4] The granulated product according to [1], wherein the average particle size of the granulated product is 200 to 450 μm,

[5] The granulated product according to [1], which is produced by a stirring granulation method under the following conditions;

1) The rotating speed of the stirring blade is 50-500rpm,

2) Stirring time is 1-10 minutes,

3) The amount of added water is 20 to 45% by weight when the charged amount is 100% by weight.

[6] One part or more selected from the group consisting of 0.02-0.15 parts by weight of low-substituted hydroxypropyl cellulose and lactose, sucrose, and mantolka per 1 part by weight of pranlukast hydrate A capsule containing a granulated product containing 0.1 to 0.6 parts by weight of the above excipient, and 12.5 mg of pranlukast hydrate contained in one capsule, Elution rate of at least 60% at 30 minutes after the start of the test, at least 85% after 120 minutes, and unpacked for 2 weeks at 25 ° C and 75% relative humidity Capsules with a difference in elution rate after and before storage of 30% or less,

[7] The capsule according to the above item [6], wherein the granulated product further contains a binder,

[8] The capsule according to [6], wherein the average tensile breaking force of the granulated product is 300 to 600 g, [9] the capsule according to [6], wherein the average particle size of the granulated product is 200 to 450 μm [10] Capsule according to item [6] above, wherein the granulated product is produced by the stirring granulation method under the following conditions: 1) The rotational speed of the stirring blade is 50 to 500 rpm, 2 ) Stirring time is 1 to 10 minutes, 3) The amount of added water is 20 to 45% by weight when the charged amount is 100% by weight.

[11] The capsule according to [7] above, comprising a granulated product and a lubricant,

[12] A pharmaceutical composition comprising pranlukast hydrate, a cellulosic disintegrant and an excipient, which dissolves quickly, exhibits stable dissolution, and has little change in dissolution rate over time. ,

[13] Elution rate of at least 40% after 30 minutes, elution rate of at least 70% after 120 minutes, and after storage for 2 weeks at 25 ° C and 75% relative humidity without packaging The pharmaceutical composition according to [12], wherein the difference in dissolution rate before storage is 30% or less,

[14] Elution rate of at least 40% after 30 minutes and at least 80% after 90 minutes The pharmaceutical composition according to [13] above, wherein the dissolution rate is 30% or less after storage for 2 weeks at a temperature of 25 ° C and a relative humidity of 75% in an unwrapped state. ,

[15] The cellulosic disintegrant is at least one selected from the group consisting of crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, and low-substituted hydroxypropylcellulose. The pharmaceutical composition according to the above item [12], which is at least one selected from the group consisting of lactose, sucrose, and mantolka

[16] The pharmaceutical composition according to [15], wherein the cellulosic disintegrant is low-substituted hydroxypropylcellulose, and the excipient is lactose;

[17] The previous item containing 0.02 to 0.2 parts by weight of a cellulosic disintegrant and 0.05 to 0.6 parts by weight of excipients per 1 part by weight of pranlukast hydrate [12] [18] The pharmaceutical composition according to the above item [12], characterized by adding a cellulosic disintegrant and granulating the force.

[19] Capsule filled with the pharmaceutical composition according to [12] above,

[20] A tablet formed by tableting the pharmaceutical composition according to [12], and

[21] A granule comprising the pharmaceutical composition according to [12] above

About.

The invention's effect

[0010] In the present invention, the elution of the pranlukast hydrate, which is an active ingredient without deteriorating the adhesion and aggregation properties, is improved by granulating using specific celluloses as a disintegrant. A granulated product can be provided. Therefore, the granulated tanned pharmaceutical composition containing the pranlukast hydrate, cellulose disintegrant and excipient of the present invention is suitable for the production of a solid preparation, and the solid preparation (tablet , Capsules, etc.), the active ingredient elutes quickly, and even if stored in an unwrapped state, the dissolution change is unlikely to occur. Therefore, it is possible to provide a solid preparation containing pranlukast hydrate having a stable quality.

Brief Description of Drawings

FIG. 1 is a graph showing the results of dissolution tests of Formulation Examples 1 to 3.

BEST MODE FOR CARRYING OUT THE INVENTION [0012] The granulated product of the present invention is a granulated product comprising pranlukast hydrate, a cellulosic disintegrant, and an excipient. For example, it is a granulated product such as a powder or a granule with little change in dissolution rate over time.

The pranlukast hydrate used in the present invention has the formula (A)

[Chemical 1]

4-oxo-8- [4- (4-Ferbutoxy) benzoylamino]-2— (tetrazol-5-yl) -4H-1 monobenzopyran 1Z2 hydrate represented by The production of pranlukast hydrate can be performed, for example, according to the method described in JP-A 61-050977.

[0014] The cellulose-based disintegrant used in the present invention includes crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium or carboxymethylcellulose. These can be used by appropriately blending one or more thereof. Preferably, low-substituted hydroxypropylcellulose or croscarmellose sodium is used. More preferred is low-substituted hydroxypropylcellulose.

[0015] The low-substituted hydroxypropyl cellulose (L-HPC) used in the present invention is distinguished from ordinary hydroxypropyl cellulose (HPC), and the hydroxypropoxyl group content in hydroxypropyl cellulose is about 5 to 16% by weight. The low-substituted hydroxypropyl cellulose is about 7 to 9.9 parts by weight, which is preferably about 7 to 13 parts by weight of the low-substituted hydroxypropyl cellulose. Particularly preferred. Specific examples of L-HPC include low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content of about 7 to 9.9 parts by weight in hydroxypropylcellulose, such as LH-22 (Shin-Etsu Chemical Co., Ltd.). Co., Ltd., average particle size of about 40 / ζ πι), LH-32 (Shin-Etsu Chemical Co., Ltd., average particle size of about 25 μm), and mixtures thereof. These are commercially available. For example, LH-21 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle diameter of about 40 m) as a low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content in hydroxypropyl cellulose of about 10.0 to 12.9 weight, LH-31 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 25 m), LH--11 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 50; ζ ΐη), LH-B1 (Shin-Etsu Chemical) Kogyo Co., Ltd., average particle diameter of about 50 m), and mixtures thereof can be mentioned, and these are available as commercial products. For example, LH-20 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 40) is used as a low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content in hydroxypropyl cellulose of about 13.0 to 16.0 weight. m), LH-30 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 25 μm), and mixtures thereof, etc., which are commercially available.

[0016] Normal hydroxypropyl cellulose (HPC) is hydroxypropyl cellulose having a hydroxypropoxyl group content of about 53.4-77.5 parts by weight in hydroxypropyl cellulose.

[0017] Examples of the excipient used in the present invention include saccharides, starches, crystalline cellulose, anhydrous calcium acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and the like. It can mix | blend and use. Preferably, saccharides are used. Examples of the saccharide include glucose, fructose, maltose, lactose, sucrose, isomerized lactose, reduced lactose, sucrose, mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol and the like. Lactose, sucrose or mannitol is preferred, and lactose is more preferred. Examples of starches include corn starch, potato starch, wheat starch, and rice starch.

[0018] The method for producing the granulated product of the present invention is in accordance with a known method, for example, pranlukast hydrate, cellulosic disintegrant, excipient, and, if necessary, other additives are mixed. Or known granulation methods (for example, extrusion granulation method, stirring granulation method, mixed stirring granulation method, high speed mixing stirring granulation method, kneading high speed stirring granulation method, fluidized bed granulation method, rolling stirring) Granulation by fluidized bed granulation method, rolling granulation method, dry (compression) granulation method, crushing granulation method, spray drying granulation method, etc.) and drying, sizing, classification, etc. as necessary Can be manufactured. Elution quickly, stable dissolution, and little change in dissolution rate over time In order to produce a composition, it is preferable to granulate by adding the above-mentioned cellulosic disintegrant. As the granulation method of the granulated product of the present invention, stirring granulation method (including mixed stirring granulation method, high speed mixed stirring granulation method, kneading high speed stirring granulation method), fluidized bed granulation method, rolling The stirring fluidized bed granulation method or the spray drying granulation method is preferable, and the stirring granulation method is particularly preferable.

[0019] The granulated product of the present invention comprises, in addition to pranlukast hydrate, a cellulosic disintegrant and an excipient, an additive generally used in producing a granulated product or a pharmaceutical composition. For example, binders, lubricants, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents. In addition, one or more elution aids, fluidizing agents and the like can be appropriately blended and used. In addition, it may contain a disintegrant other than the above-mentioned cellulose-based disintegrant, and one or more of them can be appropriately blended and used as desired.

[0020] Examples of the binder include water-soluble celluloses, povidone, polybulurpyrrolidone, polybulal alcohol, sodium carboxymethylcellulose, partially alpha-denified starch, alpha-gelatinized starch, sodium alginate, pullulan, gum arabic powder, Examples include gelatin. Water-soluble celluloses are water-soluble celluloses that have lost hydrogen bonds by substituting part of the hydrogen atoms of the hydroxyl group of cellulose with methyl, ethyl, propyl, hydroxypropyl, or hydroxyethyl groups. Is a molecule. For example, hydroxymethylenoresenorelose, hydroxyethinoremethinoresolerose, methinoresenorelose, hydroxychetylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate ( HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the like, and one or more of these may be used as appropriate. As water-soluble celluloses, V and deviation are also preferred! /, But hydroxypropylmethylcellulose or hydroxypropylcellulose (HPC) is particularly preferred.

[0021] Examples of the corrigent include sucrose, D-sorbitol, xylitol, citrate, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, -Sodium inosinate, 5,-Sodium guarate, etc. [0022] Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene 'polyoxypropylene copolymer, sodium lauryl sulfate, and the like. Can be mentioned. Examples of the fragrances include lemon oil, orange oil, menthol and brackish oil.

[0023] Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, and polyethylene dallicol.

[0024] Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow sesquioxide, and iron oxide. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like.

[0025] Examples of the concealing agent include titanium oxide.

Examples of the antistatic agent include talc and titanium oxide.

Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like.

[0026] Examples of the dissolution aid include dry methacrylic acid copolymer LD, hydroxypropyl methylenocellulose acetate succinate, hydroxypropinoremethylol cellulose phthalate, and the like.

Examples of the fluidizing agent include light caustic anhydride, talc, hydrous silicon dioxide and the like.

[0027] Disintegrants other than the above-described cellulose-based disintegrants include adipic acid, alginic acid, sodium alginate, alpha-monoized starch, sodium carboxymethyl starch, hydrous oxalic acid, licorice powder, and kanteng powder. , Guar gum, calcium citrate, glycerin fatty acid ester, croscarmellose sodium, crospovidone, light anhydrous silicate, synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, dioctyl sodium sulfosuccin Sucrose fatty acid ester, magnesium hydroxide alumina, calcium stearate, polyoxyl 40 stearate, refined white sugar, sorbitan sesquioleate gelatin, sorbitan fatty acid ester, talc, sodium bicarbonate, charcoal Magnesium acid, precipitated calcium carbonate, sodium carboxymethyl starch with low degree of substitution, dextrin, sodium dehydroacetate, corn starch, tragacanth powder, honey, potato starch, partially pregelatinized starch, monosodium fumarate, povidone, polyoxyethylene cured Castor Oil 60, Polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polyoxyethylene (160) Polyoxypropylene (30) Glycol, Polysorbate 40, Polysorbate 80, Polybulacetal Jetylaminoacetate, Macrogonore 400, Macrogonore 1500, Macrogonore 4000, Macrogonore 6000, Mantol, citrate anhydride, magnesium aluminate metasilicate, methylcellulose, glyceryl monostearate Sodium lauryl sulfate, calcium dihydrogen phosphate and the like can be mentioned, et al are.

In the present invention, the pharmaceutical composition means a composition comprising pranlukast hydrate, a cellulosic disintegrant, and an excipient. Accordingly, the pharmaceutical composition in the present invention is a composition obtained by mixing the granulated product, which may be the granulated product itself, and one or more of the other additives as described above. Moyo!

[0029] The granulated product or the pharmaceutical composition of the present invention can be suitably used for the production of a solid preparation. That is, the granulated product or the pharmaceutical composition obtained by the above method is filled or tableted by a known method, for example, “capsule filled with granulated product”, “tablet granulated product” Can be manufactured as “tablets”, “capsules filled with the pharmaceutical composition”, and “tablets formed by compressing the pharmaceutical composition”. It can also be used as a granule or powder as it is. Furthermore, tablets, powders or granules can be used as a dissolving Z suspension type preparation (for example, dry syrup) for use as a solution or suspension when taken.

[0030] "Capsule formed by filling granulated product", "tablet formed by compressing granulated product", "capsule filled with pharmaceutical composition", "formulation composition" When producing a “tablet tablet”, the granulated product is mixed with other additives such as a lubricant as necessary, and then tableted or filled into capsules.

[0031] The capsule skin of the capsule filled with the granulated product or the pharmaceutical composition of the present invention may be any conventional skin, such as gelatin or polyethylene glycol. Examples include blended gelatin, hydroxypropylmethylcellulose, pullulan and the like. The tablet may be coated with a film coating base that is pharmaceutically acceptable as necessary and does not interfere with the effects of the present invention.

[0032] As the dry syrup agent, the granulated product obtained by the above-mentioned method can be used as it is as a dry syrup agent, and if desired, a commonly used bitterness improving agent (flavoring agent) can be added and used. A dry syrup that can be taken suspended in water can be provided.

[0033] As the solid preparation in the present invention, a capsule formed by filling the granulated product of the present invention, a capsule filled with the pharmaceutical composition of the present invention, or the granulated product of the present invention. A tablet formed by tableting or a tablet formed by compressing the pharmaceutical composition of the present invention is preferred, more preferably a capsule filled with the granulated product of the present invention, and the pharmaceutical composition of the present invention. Capsenole agent filled with

[0034] Examples of other additives that may be added in the process of producing capsules filled with a granulated product, a tanned pharmaceutical composition, or tablets formed by tableting include, for example, excipients, Disintegrants, binders, fluidizers, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, flavoring agents, dissolution aids, etc. One or more selected from these may be appropriately blended and used. Excipients, disintegrants, binders, fluidizing agents, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, flavoring agents, elution aids As mentioned above, those mentioned above can be mentioned.

[0035] The content of pranlukast hydrate in the granulated product according to the present invention is preferably about 50 to about 98% by weight when the granulated product or the pharmaceutical composition is 100 parts by weight. More preferred is about 60 to about 90 parts by weight, and particularly preferred is about 60 to about 80 parts by weight.

[0036] The weight ratio of the cellulosic disintegrant to 1 part by weight of pranlukast hydrate is preferably about 0.02-0. 2 parts by weight, more preferably about 0.02 to about 0.15 parts by weight, particularly preferably about 0.07 to about 0.15 parts by weight, and particularly preferably about 0.07 parts by weight. To about 0.13 parts by weight.

[0037] Preferably, the weight ratio of the excipient to 1 part by weight of pranlukast hydrate is about 0.05 to about 0. 8 parts by weight, more preferred Or about 0.1 to about 0.6 parts by weight, particularly preferably about 0.15 to about 0.35 parts by weight.

[0038] In the granulated tanned pharmaceutical composition of the present invention, the weight ratio of the binder to 1 part by weight of pranlukast hydrate is preferably about 0.01 to about 0.00. 3 parts by weight, more preferably about 0.01 to about 0.1 part by weight, and particularly preferably about 0.01 to about 0.04 part by weight.

[0039] The content of pranlukast hydrate in the solid preparation of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, dosage form, etc., but the desired effect of the present invention is obtained. It is preferable to set so that For adults, the dose of pranlukast hydrate per day is preferably about 25 to 2500 mg, more preferably about 112.5 to 450 mg. Specifically, about 50 mg, about 70 mg, about 100 mg, about 112.5 mg, about 140 mg, about 200 mg, about 225 mg, about 280 mg or about 450 mg are preferred. For example, in the case of a capsule filled with a granulated product or a pharmaceutical composition or a tablet formed by tableting, the content of pranlukast hydrate in one capsule or one tablet is preferably about 112.5 mg. Or about 225 mg, more preferably about 112.5 mg.

[0040] Further, in order to administer the granulated product or pharmaceutical composition of the present invention to children, it is preferably used as a powder, a condyle granule or a dry syrup. The daily dose of pranlukast hydrate per kg body weight of the pediatric patient is preferably about 2 mg to about 10 mg, more preferably about 5 mg to about 8 mg, and more preferably about 7 mg. For pediatric patients weighing 12 kg or more and less than 18 kg, it is preferable to administer pranlukast hydrate from about 50 mg to about 1 OO mg per day, more preferably about 50 mg or about 1 OO mg. . For pediatric patients weighing 18 kg or more and less than 25 kg, it is preferable to administer about 70 mg to about 140 mg of pranlukast hydrate per day, more preferably about 70 mg or about 140 mg. For pediatric patients weighing 25 kg or more and less than 35 kg, it is preferable to administer pranlukast hydrate from about lOO mg to about 200 mg per day, more preferably about lOO mg or about 200 mg. For pediatric patients weighing 35 kg or more and less than 45 kg, it is preferable to administer about 140 mg to about 280 mg of pranlukast hydrate per day, more preferably about 140 mg or about 280 mg.

[0041] In the present invention, the dissolution rate is determined based on the 14th revised Japanese Pharmacopoeia General Test Method. The dissolution rate of pranlukast hydrate is calculated by conducting a dissolution test according to Method 2 (Paddle Method: 50 rpm). Specifically, 1.0% polysorbate 80-containing disintegration test solution 2 (pH 6.8, 900 mL) was selected as the test solution, a dissolution test was performed using a sinker, and the resulting sample solution was measured by the absorbance method (measurement wavelength 350 nm ) And the elution rate of pranlukast hydrate can be calculated.

[0042] In the granulated product or pharmaceutical composition of the present invention, the term "elutes quickly" means a capsule formed by filling the granulated product or pharmaceutical composition of the present invention, the granulated product or the pharmaceutical composition. Or, it means that pranlukast hydrate contained in tablets formed by tableting the granulated product or pharmaceutical composition dissolves quickly.For example, in the above dissolution test, dissolution 30 minutes after the start of the test. The index is that the power is 0% or more.

[0043] In the granulated product of the present invention, the “stable dissolution” means, for example, the granulated product or pharmaceutical composition of the present invention, the granulated product or It indicates that a capsule formed by filling a pharmaceutical composition or a tablet formed by tableting the granulated product or the pharmaceutical composition shows uniform solubility. For example, in the above dissolution test, the granulated product or the pharmaceutical composition of the present invention, the capsule filled with the granulated product or the pharmaceutical composition, or the tablet formed by compressing the granulated product or the pharmaceutical composition. The dissolution rate at 30 minutes after the start of the test is 40% or more, and the dissolution rate at 120 minutes after the start of the test is 70% or more, preferably 80% or more after 90 minutes from the start of the test. Use as an indicator. Preferably, “stable dissolution” is indicated. The dissolution rate after 30 minutes from the start of the test is 60% or more, and the dissolution rate after 120 minutes from the start of the test is 85% or more.

[0044] In the granulated product according to the present invention, it is said that “the change in dissolution rate with time is small” means the granulated product or pharmaceutical composition of the present invention and the granulated product. Furthermore, the dissolution rate changes even after the capsules filled with the pharmaceutical composition or the tablets formed by squeezing the granulated product and the pharmaceutical composition are stored for a certain period of time under warming and Z or humidification conditions. Or no change in dissolution rate. For example, the granulated product or pharmaceutical composition of the present invention stored in a non-packed state at a temperature of 25 ° C. and a relative humidity of 75% for 2 weeks, a capsule filled with the granulated product or the pharmaceutical composition, or the granulated product The above dissolution test was conducted on tablets formed by compressing the tablet! / Drug formulation composition, and the difference in dissolution rate was preferably 30% or less, preferably compared with that before storage. Is 20% or less, more preferably 15% or less. The difference in dissolution rate is the dissolution rate measured at a given measurement time before storage in C (%) and the same after storage for 2 weeks.

0

Means the difference between C (%) and C (%) when the dissolution rate measured over the measurement time is C (%)

2 0 2

To do. Therefore, “less change in dissolution rate over time” means that the absolute value of C—C is 30% or less.

0 2

The lower index is preferably 20% or less, more preferably 15% or less.

[0045] In the present invention, the ability to achieve the object of improving the solubility without greatly exacerbating the adhesion and agglomeration of the granulated product. As one index for achieving the object in that way, The average tensile breaking strength of the granulated product can be employed. The average tensile breaking strength of the granulated product of the present invention is preferably about 300 to about 600 g, more preferably about 300 to about 450 g, and particularly preferably about 350 to about 450 g. If the average tensile rupture force of the granulated product is less than 300 g, the adhesion / aggregation property is small, but the elution property tends to decrease, which is not preferable. On the other hand, if it exceeds 600 g, adhesion and cohesiveness increase, which may cause problems in the production and use of the granulated product.

In the present invention, the average tensile rupture force is calculated by a compression property / adhesion property measuring device (trade name: TAG Robot, manufactured by Hosokawa Micron Corporation).

It has long been known that adhesion 'aggregation between particles is caused by the following forces. 1) intermolecular force between solid particles, 2) binding force on the particle surface, 3) electrostatic charge force, 4) surface tension due to interparticle liquid cross-linking, binding force due to capillary negative pressure, 5) binding force due to binder, 6) High temperature • Bonding due to melting of particles under high pressure. As a method for comprehensively measuring these parameters, several apparatuses that measure relatively small adhesion and cohesion using a low-pressure densely divided cell are known. However, in the method using a low-pressure dense two-divided cell, the measurement range is insufficient and stable measurement is difficult. The Tag Robot (trade name) is a device that can perform stable measurements in the high-pressure and dense areas handled by powder mixing and granulation operations, which were difficult to measure with existing devices.

[0047] The tensile rupture force σ (Ftb, g) of the powder layer is expressed by the Rumpf equation

[Number 1]

It is defined by the particle diameter Xp, the powder layer structure (spatial ratio ε, coordination number k), and interparticle adhesion force H, and is one of the indices indicating adhesion. .

[0048] The average particle size of the granulated product of the present invention is about 200 to about 450 μm, more preferably about 250 to about 370 μm, and particularly preferably about 300 to 370 μm. .

In the present invention, the average particle diameter of the granulated product means the cumulative 50% average particle diameter (weight-based average diameter) of the powder particles. The average particle size in the present invention is, for example, a dry type V, and an ultrasonic vibration type fully automatic particle size distribution measuring device (Robot Shifter, manufactured by Seishin Enterprise), which is a separate measuring device, with a set step force of 6 steps. , 24, 32, 60, 100, 150, and 200 can be used.

[0049] The bulk density of the granulated product of the present invention is preferably about 0.4 to about 0.65 gZmL, more preferably about 0.53 to about 0.59 gZmL.

In the present invention, the “bulk density of the granulated product” means a value (loose bulk density) obtained by dividing the “weight of the granulated product” by the “volume when the granulated product is put in a container”. For example, a sample of about 30 g is accurately weighed, placed in a dry graduated cylinder without being compacted, read to the smallest unit of the scale, and the weight of the granulated product divided by the final bulk volume of the granulated product is bulky. It can be measured by the density method.

[0050] In order to achieve the object of the present invention, it is also preferable to perform granulation by a stirring granulation (wet high shear granulation) method under the following conditions.

1) The rotation speed of the stirring blade is preferably 50 to 500 rpm, more preferably 100 to 350 rpm, and particularly preferably 250 to 350 rpm.

2) Stirring time is preferably 1 to: more preferably 1 to 5 minutes, more preferably 1 to 3 minutes. The stirring time in the present invention is a time during which the granulating liquid is added to the granulating powder and the granulating powder is stirred in a wet state. As the granulation liquid, water (purified water), hydrous ethanol, absolute ethanol, a mixture thereof, or the like can be used, or a binder or the like can be dissolved or suspended in these.

3) The amount of water added is preferably about 20 to about 45% by weight, preferably about 20 to about 35% by weight, and more preferably about 24 to about 30% by weight when the charged amount is 100% by weight. It is. The amount charged is pranlukast hydrate and cellulose before starting stirring. It means the total weight of the system disintegrant, excipient, and other additives added as necessary.

[0051] The agitation granulator includes a vertical granulator (manufactured by Baurec Co., Ltd.), a kneading high speed agitation granulator SPG (manufactured by Dalton), a flow jet duller-ureter FJG (manufactured by Okawara Seisakusho), Dalton), Bole Baguille Meter VMA (manufactured by Kotobuki Kogyo), high-speed agitating mixing granulator NMG (manufactured by Nara Machinery Co., Ltd.), high-speed mixer (manufactured by Fukae Bautech), Diosna agitating and mixing granulator (manufactured by mutual) ), New Speed-Idar (manufactured by Seida Okada), etc. Preferred are a vertical calender-ureter, a kneading high speed agitation granulator SPG, a high speed agitation type mixing granulator NMG, and a high speed mixer.

[0052] [Application to pharmaceutical products]

The granulated or non-granulated pharmaceutical composition of the present invention contains pranlukast hydrate as an active ingredient, so that respiratory respiration such as bronchial asthma, allergic rhinitis, sinusitis, COPD (chronic obstructive pulmonary disease), etc. It is useful as a preventive and Z or therapeutic agent for various diseases such as organ disease, Meniere's disease, exudative otitis media, migraine, cough, and dysmenorrhea.

[0053] [Toxicity]

The granulated product or pharmaceutical composition containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.

Example

[0054] Hereinafter, the present invention will be described in detail by way of examples, but it is for the purpose of understanding the present invention well, and the present invention is not limited thereto.

[0055] [Formulation Example 1]

Pranlukast hydrate (787.5g) and lactose (175. Og; LACTOSE NEW ZEALAND) in the container of the stirring granulator (FM—VG—10P type Vertical Caldera-Yureter, manufactured by Parek Co., Ltd.) ), Low-substituted hydroxypropyl cellulose (L—HPC) (70. Og; “LH—22” manufactured by Shin-Etsu Chemical Co., Ltd.), and hydroxypropyl methylcellulose (22.4 g; Shin-Etsu Chemical) “TC-5EW” manufactured by Co., Ltd. was added and mixed for about 1 minute, then purified water (about 27.5% by weight with respect to the charged amount) was added to the mixture, and pranlukast hydrate was added. (A blade rotation speed: 300 rpm, a chopper rotation speed: 2500 rpm, and a stirring time of about 2 minutes). Using a wet bed granulator (STREA-1, manufactured by Baurec Co., Ltd.) The air was dried at a supply air temperature of 85 ° C until the exhaust heat temperature reached 40 ° C. This dried product is sieved using a standard sieve (aperture: 1.OOmm), and granulated granulated pranlukast hydrate (VG product, average particle size 351.6 m, loose bulk density 0.56 g / mL). Obtained. After adding magnesium stearate (6. Og; manufactured by Taihei Sogaku Sangyo Co., Ltd.) to this VG product (400. Og), bag mixing was performed to obtain a powder for capsule filling. This powdered powder is filled into No. 3 capsules using a capsule filling machine (LIQFILsuper40, Qualikibusu Co., Ltd.), and cellulose disintegrant is added to about 0.089 parts per 1 part by weight of pranlukast hydrate. Capsule 1 having the following formulation and containing about 0.22 parts by weight of excipient and excipient was produced.

Granulated material

Pranlukast Hydrate 112. 5mg

Lactose (excipient) 25. Omg

L-HPC (Cellulose disintegrant) 10. Omg

TC-5 EW (Binder: Water-soluble cellulose) 3. 2mg

Additive

Magnesium stearate (lubricant) 2.3 mg

5 ~ 卜 153. Omg

[Formulation Example 2]

The same procedure as in Production Example 1 was carried out except that purified water was used in an amount of about 22% by weight, the low-substituted hydroxypropyl cellulose was not used, and the amount of magnesium stearate was changed. Thus, Capsule 2 having the following formulation was produced, which did not contain a cellulose-based disintegrant and contained about 0.22 parts by weight of excipients per 1 part by weight of pranlukast hydrate. The average particle size of the granulated product was 380. The loose bulk density was 0.61 gz mL.

Granulated material

Pranlukast Hydrate 112. 5mg

Lactose (excipient) 25. Omg

TC— 5 EW (Binder: Water-soluble celluloses) 3. Omg

Additive

Magnesium stearate (lubricant) 2. lmg

Total 142. 6 mg

[Formulation Example 3] Purified cast hydrate is added to 1 part by weight by using the same procedure as in Production Example 1, using approximately 36% by weight of purified water with respect to the charged amount, and appropriately changing the amount of cellulosic disintegrant and other agents. On the other hand, capsule 3 containing about 0.22 parts by weight of a cellulosic disintegrant and about 0.22 parts by weight of a saccharide was prepared. The average particle size of the granulated product is 263

.3 / zm and loose bulk density. It was .51g / no

Granulated material

Pranlukast hydrate 1 12.5mg

Lactose (excipient) 25. 0 mg

L-HPC (Cellulose disintegrant) 25.0 mg

TC-5 EW (binder: water-soluble cell mouth) 3.5 mg

Additive

Magnesium stearate (lubricant) 2.5 mg

168.5mg total

[0058] [Formulation Example 4]

By using approximately 25% by weight of purified water with respect to the charged amount and changing the amount of excipients and other agents used as appropriate, the same procedure as in Formulation Example 1 was performed, so that 1 part by weight of pranlukast A capsule 4 containing about 0.089 parts by weight of a loin disintegrant and about 0.089 parts by weight of an excipient was prepared. The average particle size of the granulated product was 415.9 m, and the loose bulk density was 0.38 gZmL.

Granulated material

Pranlukast hydrate 1 12.5mg

Lactose (excipient) 10. Omg

L-HPC (Cellulose disintegrant) 10. Omg

TC-5 EW (Binder: Water-soluble cellulose) 3. 2mg

Additive

Magnesium stearate (lubricant) 2. 1 mg

Total 137.8mg

[0059] [Formulation Example 5]

Purified cast is used in an amount of about 26% by weight of purified water, and the amount of excipients and other agents used is changed as appropriate. A capsule 5 containing about 0.089 parts by weight of a loin disintegrant and about 0.31 parts by weight of a saccharide was prepared. The average particle size of the granulated product is 294.9 μm, The bulk density was 0.57 gZmL.

Granulated material

Pranlukast Hydrate 112. 5mg

Lactose (excipient) 35. Omg

L-HPC (Cellulose disintegrant) 10. Omg

TC-5 EW (Binder: Water-soluble cellulose) 3. 2mg

Additive

Magnesium stearate (lubricant) 2.4 mg

Total 163.1 mg

[0060] [Measurement of tensile breaking force]

In order to evaluate the adherence of the granules contained in the capsules produced in Production Examples 1 to 3, the tensile breaking force was measured with a Hogagawa Micron Co., Ltd. tag robot (trade name; model AGR-2). The measurement conditions of the flag robot are as follows:

'Senore ID: 25mm

'Cell temperature: 25 ° C

'Pane wire diameter: 1.2mm

'Compression speed: 0. ImmZ seconds

• Maximum compression force: 150kgf

• Compression retention time: 60 seconds

• Tensile sampling time: 25 seconds

[0061] The measurement was performed three times for each granulated product, and the average value was obtained.

. In Table 1, L-HPC parts by weight means parts by weight of L HPC in the case of 1 part by weight of pranlukast hydrate in the granulated product.

[0062] [Table 1]

[0063] From the above results, the tensile breaking strength is increased by increasing the amount of L-HPC contained in the granulated product. Was found to decrease. In the combination of pranlukast hydrate, which is a highly cohesive drug, and L-HPC, which is a highly viscous cellulosic disintegrant, if the amount of L-HPC is increased, pranlukast hydrate adheres The force that was thought to exacerbate the gender.

[0064] [Elution evaluation 1]

The capsules produced in Formulation Examples 1 to 3 were subjected to a dissolution test in the second disintegration test solution (pH 6.8) containing 1.0% polysorbate 80. The test was conducted using a sinker in accordance with the 14th revised Japanese Pharmacopoeia general test method, dissolution test method method 2 (paddle method: 50 rpm). The test solution was a solution prepared by adding 1.0% polysorbate 80 to the second disintegration test solution (pH 6.8). The sampled solution was measured by the absorbance method (measurement wavelength: 350 nm), and the elution rate was calculated. The results are shown in Table 2 and FIG.

[0065] [Table 2]

[0066] As is clear from the above results, formulation example 1 is about 73% 30 minutes after the start of the disintegration test,

The dissolution rate was about 93% after 120 minutes, and the dissolution rate was clearly improved as compared with Formulation Example 2 and Formulation Example 3.

[0067] When the results of the dissolution test were considered together with the measurement results of the tensile breaking force described above, formulation example 3 having a relatively low adhesion and a high disintegrant content was found in the solution. However, the above results were contrary to the above results. Capsule 1 produced in Formulation Example 1 showed the best dissolution properties.

For this reason, in the combination of pranlukast hydrate and cellulosic disintegrant

It was revealed that the elution rate of pranlukast hydrate can be particularly improved by setting the cellulose disintegrant content to a specific value (Formulation Example 1).

[0068] [Dissolution Evaluation 2 (Stability Test)]

Capsule 1 manufactured in Formulation Example 1 was unwrapped and kept at 25 ° C and 75% relative humidity After storing in a humidity chamber for 2 weeks, the dissolution rate was measured in the same manner as in the above dissolution evaluation 1. Table 3 shows the difference (%) relative to the dissolution rate before storage.

[0069] [Table 3]

[0070] Based on the above, Capsule 1 produced in Formulation Example 1 has a difference in elution rate (decrease) compared to before storage even after storage in a non-packaging state for a certain period under humidified conditions. However, it was clarified that it was a formulation with little change in dissolution rate over time.

[0071] [Elution evaluation 3]

The dissolution rate in the capsules produced in Formulation Examples 1, 4 and 5 was calculated by conducting a dissolution test similar to the above-described dissolution evaluation 1. The results are shown in Table 4.

[0072] [Table 4]

[0073] In Formulation Examples 4, 1 and 5, the weight part of the cellulosic disintegrant relative to 1 part by weight of pranlukast hydrate is constant, whereas the weight part of the excipient (Formulation Example 4: 0. 089, Formulation Example 1: 0.22, Formulation Example 5: 0.31) are different.

From the above results, it is clear that the capsules produced in Formulation Example 1 and Formulation Example 5 are superior in dissolution properties compared to the capsules produced in Formulation Example 4, and therefore, pranlukast hydrate and Even in the combination of excipients, it is clear that the dissolution rate of pranlukast hydrate can be improved by setting the content of excipient to pranlukast hydrate to a specific value. It became.

[0074] [Formulation Example 6]

Preliminary hydroxypropyl methylcellulose (157.5 g; Shin-Etsu Chemical “TC-5EW” manufactured by Kogyo Co., Ltd. was dissolved in purified water (2092.5 g) to obtain a binding solution. Pranlukast hydrate (750. Og) and lactose (166.7 g; LACTOSE NEW ZE ALAND) in a container of a stirring granulator (FM-VG-10P type vertical caldera-ureter, manufactured by Norec Co., Ltd.) After mixing for 1 minute, an appropriate amount of the binding solution prepared above was added to the mixture to obtain a wet product of pranlukast hydrate (blade rotation speed: 300 rpm, chopper rotation speed: 2500rpm). This wet product was dried using a fluidized bed granulator (STREA-1, manufactured by Baurec Co., Ltd.) at a supply air temperature of 85 ° C until the exhaust heat temperature reached 40 ° C. This dried product was sieved using a standard sieve (aperture: 1.00 mm) to obtain a granulated product (VG product) of pranlukast hydrate. In this VG product (368. Og), low-substituted hydroxypropyl cellulose (L—HPC) (26. Og; “LH-22” manufactured by Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (6 (Og: Taihei Sogaku Sangyo Co., Ltd.) was added, and the mixture was mixed with a bag to obtain a capsule filling powder. This powdered powder was filled into No. 3 capsules with a capsule filling machine (LIQFILsuper40, manufactured by Qualicaps Co., Ltd.), and capsule 6 was produced by adding a cellulose-based disintegrant after granulation.

Granulated material

Pranlukast hydrate 11 2.5 mg

Lactose (excipient) 2 5. Omg

TC-5 EW (Binder:: Water-soluble cellulose) 2. 4mg

Additive

L-HPC (disintegrant) 1 0. Omg

Magnesium stearate (lubricant) 2. 3mg

Total 15 2. 2 mg

[Elution evaluation 4]

By conducting the same dissolution test as in the above-mentioned dissolution evaluation 1, the dissolution rate in the capsule prepared in Preparation Example 6 was calculated. When the results were compared with the results for Formulation Examples 1 and 2, a formulation containing no cellulosic disintegrant (Formulation Example 2) or a formulation prepared by adding a cellulosic disintegrant after granulation (Formulation Example 6) ) At any measurement time, elution of pranlukast hydrate was less than that of the preparation (Formulation Example 1) produced using the granulated product of the present invention containing a cellulosic disintegrant. I was slow. From the above, in order to improve the dissolution property, it is preferable to add a cellulose-based disintegrant and granulate the force. It became clear.

Industrial applicability

In solid preparations (tablets, capsules, etc.) produced using the granulated product of the present invention, the active ingredient dissolves quickly and exhibits stable dissolution. It does not affect the overall availability. Therefore, it is possible to provide biologically equivalent and stable quality preparations.

Claims

The scope of the claims

[I] One part by weight of pranlukast hydrate is 0.02-0.15 parts by weight of low-substituted hydroxypropylcellulose and at least one selected from the group consisting of lactose, sucrose, and mantolka A granulated product containing 0.1 to 0.6 part by weight of excipient, which dissolves rapidly, exhibits stable dissolution, and has little change in dissolution rate over time.

[2] The granulated product according to claim 1, further comprising a binder.

[3] The granulated product according to claim 1 having an average tensile breaking strength of 300 to 600 g.

[4] The granulated product according to claim 1, wherein the granulated product has an average particle size of 200 to 450 μm.

[5] The granulated product according to claim 1, which is produced by a stirring granulation method under the following conditions; 1) the rotational speed of the stirring blade is 50 to 500 rpm, and 2) the stirring time 1 to 10 minutes, 3) The amount of added water is 20 to 45% by weight when the charge is 100% by weight.

[6] One part by weight of pranlukast hydrate is 0.02 to 0.15 parts by weight of low-substituted hydroxypropylcellulose and at least one selected from the group consisting of lactose, sucrose and mantolka A capsule containing a granulated product containing 0.1 to 0.6 parts by weight of excipient, and 12.5 mg of pranlukast hydrate contained in one capsule, and in the dissolution test, Elution rate of at least 60% 30 minutes after the start of the test, at least 85% elution rate after 120 minutes, and after storage for 2 weeks at 25 ° C and 75% relative humidity without packaging Capsules whose previous dissolution rate difference is 30% or less.

[7] The capsule according to claim 6, wherein the granulated product further contains a binder.

[8] The capsule according to claim 6, wherein the granulated product has an average tensile breaking strength of 300 to 600 g.

[9] The capsule according to claim 6, wherein the granulated product has an average particle size of 250 to 370 μm.

[10] Capsule according to claim 6, wherein the granulated product is produced by a stirring granulation method under the following conditions; 1) The rotational speed of the stirring blade is 50 to 500 rpm, 2) The stirring time is 1 to 10 minutes. 3) The amount of added water is 20 to 45% by weight when the charged amount is 100% by weight.

[II] The capsule according to claim 7, comprising a granulated product and a lubricant.

[12] A pharmaceutical composition comprising pranlukast hydrate, a cellulosic disintegrant and an excipient, which dissolves rapidly, exhibits stable dissolution, and has little change in dissolution rate over time.

[13] Elution rate of at least 40% after 30 minutes, at least 70% after 120 minutes, and unpacked at 25 ° C and 75% relative humidity for 2 weeks 13. The pharmaceutical composition according to claim 12, wherein the difference in the previous dissolution rate is 30% or less.

[14] Elution rate of at least 40% after 30 minutes, elution rate of at least 80% after 90 minutes, and after storage for 2 weeks at 25 ° C and 75% relative humidity without packaging. 14. The pharmaceutical composition according to claim 13, wherein the difference in dissolution rate before storage is 30% or less.

[15] The cellulosic disintegrant is one or more selected from the group consisting of crystalline cellulose, carmellose, carmellose calcium, strength rumellose sodium, croscarmellose sodium, and low-substituted hydroxypropylcellulose strength, and an excipient 13. The pharmaceutical composition according to claim 12, which is at least one selected from the group consisting of lactose, sucrose and mantolka.

16. The pharmaceutical composition according to claim 15, wherein the cellulosic disintegrant is low-substituted hydroxypropylcellulose and the excipient is lactose.

[17] Cellulose disintegrant 0.02 to 0.2 parts by weight per 1 part by weight of pranlukast hydrate

The pharmaceutical composition according to claim 12, comprising 0.05 to 0.6 parts by weight of an excipient.

[18] The pharmaceutical composition according to claim 12, wherein a cellulose-based disintegrant is added to granulate the force.

[19] A capsule filled with the pharmaceutical composition according to claim 12.

[20] A tablet formed by compressing the pharmaceutical composition according to claim 12.

[21] A granule that also has the power of a pharmaceutical composition according to claim 12.